It is known that N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]heptanedicarboximide hydrochloride (hereinafter, optionally referred to as “Compound 1”) has psychotropic activity and is useful as a therapeutic agent for diseases such as schizophrenia. Patent Reference 1 describes that Compound 1 is usually administered orally.
It is known that risperidone, olanzapine, aripiprazole, etc. have been already used in clinical practice as an agent for treating schizophrenia or other similar diseases. In order to promote patient compliance and reduce the relapse rate of schizophrenia, these medicaments for treating schizophrenia are desired to be modified to exert a long-term effect through a single administration.
A depot formulation for intramuscular injection comprising an injectable suspension of a medicament is generally known as one of administration means for sustained-release of a medicament. An injectable suspension is in a heterogeneous system comprising a solid phase dispersed in an aqueous or nonaqueous liquid phase, which requires sterile, stable, resuspendable, syringeable, injectable, isotonic, and nonirritating. In order to develop such depot formulation, in particular, it is necessary at least that such formulation is an aqueous one and additionally has satisfactory properties for an injectable suspension such as uniformity of dispersed particles of an active ingredient, sedimentation property of dispersed particles after still standing, re-suspensibility, and permeability in a needle (hereinafter, optionally referred to as “suspensibility”). In order to satisfy these requirements, for example, Patent Reference 2 discloses a composition comprising microparticles comprising a polymeric binder, and an aqueous injectable vehicle. The composition has a constructional property wherein the microparticles have a mass median diameter of at least about 10 μm, and the vehicle comprises a viscosity enhancing agent.
However, many of medicaments for treating schizophrenia or other similar diseases are hardly water-soluble, thus it is not easy to develop such formulation thereof which can make these requirements satisfied.
For example, a formulation comprising aripiprazole makes such requirements satisfied by reducing the mean particle size of the compound and adding a specific suspending agent such as carboxymethylcellulose thereto (Patent Reference 3). And, a formulation comprising olanzapine makes such requirements satisfied by further reducing the size of the compound to nanoparticles and using a surface stabilizer such as polysorbate (Patent Reference 4). As just described, in order to prepare a suspension comprising such hardly water-soluble compound, it is necessary to select an adaptable means in response to the property of the active ingredient after studying various means to meet the requirements.
To prepare a formulation for injection, some extra processes such as sterilization and dust free in a clean room are also required. In particular, a process under aseptic atmosphere is generally accompanied with some complicated and troublesome steps and manufacturing-operations. In addition, to comply with the predetermined level for assurance of aseptic preparation, some strict controls such as sterilization of apparatuses and devices, education and training for operators, and control of the number of environmental microbials and microparticles in an aseptic plant are also required.